Project Summary A significant proportion of World Trade Center (WTC) rescue and recovery workers continue to suffer from clinically significant WTC-related PTSD symptoms more than a decade after the 9/11/01 attacks. While cognitive behavioral therapy (CBT) is the most effective and empirically supported of currently available treatments for PTSD, the provision of this treatment to WTC workers is often limited by geographical distance, reduced availability of expertly trained therapists, and stigma associated with seeking formal mental health treatment in this population. Thus, there is an imperative need for treatment approaches that enhance access to CBT while preserving the effectiveness of key aspects of this treatment, such as therapeutic alliance. Internet-based CBT is an emerging treatment for PTSD that has demonstrated high treatment adherence, therapeutic alliance, and large magnitude reductions in PTSD symptoms in initial studies of other trauma survivor populations. If shown to be effective in WTC workers, Internet-based CBT (IBCBT) has the potential to reach many symptomatic workers who have encountered obstacles to mental health treatment. We propose to conduct a randomized controlled trial of Internet-based, therapist-assisted, CBT in WTC rescue and recovery workers with clinically significant WTC-related PTSD symptoms, compared to a control intervention of Internet- based, therapist-assisted supportive counseling. We plan to achieve a sample size of n = 90 study completers, n = 45 randomized to each treatment condition. To the best of our knowledge, the proposed RCT will be the first to evaluate the efficacy of IBCBT in this population, and one of the first to compare IBCBT for PTSD symptoms to an active control condition. We will additionally evaluate the efficacy of this intervention in enhancing functioning, quality of life, and posttraumatic growth in this population. A separable but complementary aim of the proposed study is to evaluate: (A) baseline genetic and epigenetic predictors of treatment response and (B) the capacity of Internet-based psychotherapy to induce changes in epigenetic regulation of genes implicated in risk for PTSD. For this aim, we will collect saliva samples pre- and post-treatment, to conduct genotyping studies of genes previously associated with PTSD in trauma-exposed samples, and measure methylation levels in a subset of those genes that is thought to operate in peripheral tissue, including NR3C1, FKBP5, 5-HTTLPR and BDNF. Gene expression validation studies will be conducted on genes with significant genetic and/or epigenetic findings. We will additionally bank samples for future genome-wide assays and include our data in meta-analyses conducted by the Psychiatric Genomics Consortium PTSD working group. Results will have the potential to identify objective biomarkers of Internet- based CBT treatment response, as well as to inform treatment matching and advance understanding of biological mechanisms of Internet-based psychotherapy among symptomatic WTC and other disaster responders.